Project Summary: The current epidemic of obesity and obesity-related disorders are presenting major public health challenges. The identification of new therapeutic strategies for regulating energy intake, absorption, and storage is therefore an important goal. The complex microbial community residing within the digestive tract has recently been shown to be an important environmental factor regulating host energy storage. I have developed a new gnotobiotic zebrafish model system, and used it to show that the roles of the microbiota in modulation of host nutrient metabolism have been evolutionary conserved between zebrafish and mammals. The long-term objective of this project is to understand the molecular mechanisms underlying microbial regulation of host nutrient metabolism. This project aims to identify the microbial factors that influence host nutrient metabolism using the gnotobiotic zebrafish model, taking advantage of its capacity for in vivo observation of host tissues, and for genetic and chemical screens. To provide a context for interpreting results from genetic and chemical screens, our limited understanding of nutrient metabolism in zebrafish needs to be expanded. In Specific Aim 1, I will assay gene expression, lipid content, and enzymatic activities to locate specific metabolic activities in developing and adult zebrafish. The microbial products and genes responsible for modulation of host energy storage are unknown, and represent potential therapeutic targets. In Specific Aim 2, these microbial factors will be identified through chemical and genetic screens in gnotobiotic zebrafish, and then validated in gnotobiotic mice. This project will establish a foundation for future studies and will lead to a more extensive understanding of the molecular mechanisms underlying host-microbial interactions in the vertebrate digestive tract. Relevance: Fat storage is influenced by the large community of microorganisms residing in the intestine. This goal of this research is to understand how intestinal microorganisms regulate fat storage. This new knowledge could lead to novel therapies for treatment of obesity and obesity-related diseases.